Method of preparing controlled long-acting pharmaceutical formulations in unit dosage form having uniform and comparable bioavailability characteristics

ABSTRACT

A method of preparing a multiplicity of controlled, long-acting release pharmaceutical tablets, each containing a therapeutic agent and a cellulosic ether carrier base material is shown. The method includes the steps of adding a quantity of cellulose ether base material such as hydroxypropyl methylcellulose and an active therapeutic agent to form a mixture, thoroughly and uniformly mixing that mixture, discontinuing the mixing, permitting the uniform mixture to stand for a period of time, typically two to twenty-four hours or longer, sufficient to cause the therapeutic agent to become bonded to the carrier base material and compressing portions of the mixture to form the solid unit dose tablets. The advantage of the method is that the time release of each tablet from a given batch of formulation and the time release characteristics of tablets prepared in different batches, will be substantially more uniform and comparable.

BACKGROUND OF THE INVENTION

I. Field of The Invention

This invention relates to a method of preparing a controlled long-actingrelease pharmaceutical formulation containing an active therapeuticagent and a carrier base material in unit dosage form. Morespecifically, this invention relates to a method of preparing batches ofunit doses of oral tablets of a controlled long-acting pharmaceuticalformulation containing an active therapeutic agent and a carrier basematerial, wherein each of the unit doses has a substantially comparableand uniform bioavailability characteristic when consumed. The inventionalso relates to the improved unit dosage forms prepared by the method ofthe invention.

This invention relates broadly to controlled long-acting pharmaceuticalformulations containing a variety of active therapeutic agents andcarrier base materials consisting of at least one cellulose ether. Thecellulose ethers typically used in the methods and compositions of theinvention are hydroxyalkyl celluloses or hydroxyalkyl alkylcellulosematerials such as hydroxypropyl methylcellulose and similar analogs.

Long-acting products are widely marketed in the pharmaceutical field andare now a significant factor in the administration of a variety ofactive pharmaceutical agents. The advantages of such long-acting orsustained release products are now well understood and a verysubstantial industry has developed around these products. Sustainedrelease products permit various medications to be administered foruniform and continuous release over a prolonged period of time therebyachieving a particular blood level of active ingredient for whatevertime is thought to be advantageous to the patient. Such administrationobviates the necessity for requiring frequent administration of activeingredient and avoids the problems inherent in insuring timely andrepetitive consumption of pharmaceutical product by the patient. It ispossible to achieve stable blood levels of a variety of activetherapeutic agents and thereby control a variety of physiologicalconditions. It also reduces or possibly eliminates toxic or side effectswhich are caused by frequent administration of active ingredientsthrough the peaks and valleys of blood levels caused by multipleingestion of medication.

II. Description of The Prior Art

The use of cellulosic derivatives, more particularly cellulose etherssuch as hydroxypropyl methylcellulose as a carrier in long-acting orsustained release pharmaceutical formulations is well known. A varietyof commercial forms of cellulosic ethers are commercially available andthese include methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, carboxymethyl cellulose and hydroxypropyl cellulose, andderivatives, among others. These cellulose ethers are each available ina range of molecular weights and viscosities and under a variety oftrade names.

Hydroxypropyl methylcellulose is a particularly preferred celluloseether for the sustained release compositions of the invention and it isavailable from Dow Chemical Company under the METHOCEL trademark. Theseveral hydroxypropyl methylcellulose products have varying methoxyl andhydroxypropoxyl contents as well as different molecular weights.Typically, the methoxyl content ranges from 16.5 to 30 weight percentand the hydroxypropyl content ranges from 4 to 32 weight percent. Theviscosities of the several grades of hydroxypropyl methylcellulose, ascalculated based on the viscosity of a 2% aqueous solution at 20° C.,range from 5 cps to 100,000 cps. Typically the higher viscosity gradematerials dissolve more slowly and can be used in lesser amounts thancomparable materials having lesser viscosities.

The prior art dates back to about the 1960's. Christiansen et. al., U.S.Pat. No. 3,065,143, disclosed the use of hydroxypropyl methylcellulosein sustained release tablets. Lowey et al., in U.S. Pat. No. 3,870,790,disclosed processes for mixing an active therapeutic ingredient withpremoisturized hydroxypropyl methylcellulose which could also optionallybe mixed with ethylcellulose. The sustained release properties of theresulting mixture could be controlled by the moisture content of thecarrier material which was in turn set in a moisturizing process whereinthe carrier material was subjected to elevated temperature and humidityconditions.

Lowey, U.S. Pat. No. 4,259,314, disclosed sustained release productswhich consisted of mixtures of hydroxypropyl methylcellulose having aviscosity of from 50 to 4,000 cps and hydroxypropyl cellulose. Thesemixtures, particularly when dried to less than one percent moisture,were advantageously used with hygroscopic active agents.

Other workers, including Schor et al., U.S. Pat. No. 4,389,393, havedisclosed sustained release compositions wherein the carrier basematerial is selected from certain preferred forms of hydroxypropylmethylcellulose having certain defined viscosities, methoxyl contents,hydroxypropyl contents and number average molecular weights.

In preparing tablets according to prior art methods, the carrier basematerial is first prepared. A mixture of cellulosic components can beemployed and, if deemed desirable, the carrier base mixture can betreated by humidification or other process steps. The active ingredientis then added to the carrier base material and thoroughly intermixedwith the base to form a uniform mixture. The mixture of activeingredient and carrier is removed to the hopper of a tableting machine.Such machines are well known in the art and may have variable sizepunches preset and are adjustable to control the compression of thetablet. For example, punches and dies from 5/32 to 1/4 inches can beemployed and the tableting machines may be adjusted to vary thecompressive pressure from 6 to 14 kg/cm². These variables and thecontrol of them are well understood in the prior art and it isrecognized that sustained release properties are a function both of thesize of the tablet and the compression to which it is subjected. Thus1/4 to 15 grain tablets can be produced according to prior art mehods.

It is of considerable importance in the administration of controlled,long-acting release pharmaceutical tablets, lozenges and the like, thatthe rate of release of the active agent from the tablet be consistentand uniform among tablets prepared in a given manufacturing batch andamong tablets prepared at different times in different manufacturingbatches. It is critical, both from the standpoint of the safety of theadministration of the therapeutic agent as well as the reliabilitythereof, that the bioavailability characteristic of the tablets preparedbe substantially uniform and comparable. In the absence of suchreliability, the dangers to a patient are significant because activeingredient may be release at faster or slower rates than are assumed.For example, where nitroglycerin is being administered to anginapatients via oral or buccal tablets, such variation in release may belife-threatening. The problem of noncomparable release rates amongpresumably identical tablets is particularly exacerbated where thosetablets are of the "one-a-day" type and where the patient is relyingupon a uniform and comparable release day after day from these tablets.

A problem that has confronted the art is that of preparing multiplelong-acting tablets wherein each tablet releases the active ingredientuniformly and comparably. To achieve the proper bioavailability ofactive ingredient over time from tablet to tablet and from batch tobatch requires not only that the same amount of active ingredient beincorporated within each tablet but that the active ingredient bethoroughly mixed and bonded to the cellulosic carrier base material inthe same manner so that release is not faster from one tablet than fromanother.

SUMMARY OF THE INVENTION

It is a primary object of this invention to provide a method forpreparing controlled, long-acting pharmaceutical formulations containingactive therapeutic agent and carrier base material, in unit dosage form,as an oral tablet which insures that the unit dosage form has uniformand comparable bioavailability characteristics.

Another object of this invention is to provide a method for preparing amultiplicity of unit doses of a controlled, long-acting releasepharmaceutical formulation which unit doses are safer and more reliableto administer to patients.

It is still a further object of this invention to prepare unit dosageforms of sustained action pharmaceutical formulations which have theadvantage of greater uniformity of bioavailability.

These and other objects of the invention are achieved in a methodwherein a carrier base material comprising at least one cellulose etheris thoroughly mixed with an active therapeutic agent to form asubstantially uniform pharmaceutical formulation, the mixing isthereafter discontinued, the so-formed mixture is permitted to stand fora period of time sufficient to cause the therapeutic agent to becomebonded to the cellulose ether (a step referred to herein as tempering)and the so-tempered pharmaceutical formulation is shaped and compressedinto a suitable unit dosage form.

The objects of the invention are achieved where a quantity of solidcarrier base material consisting essentially of one or more celluloseethers selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose andethyl cellulose or derivatives are intermixed with a therapeuticallyactive pharmaceutical agent in granular or powder form, the mixture ismechanically stirred until the agent and the base material are uniform,the mixing step is discontinued and the uniform mixture is permitted toreside for a period of time, typically two to twenty-four hours orlonger, sufficient to cause the granules of therapeutic agent to becomebonded by a physical and/or physical-chemical adherence to the particlesof carrier base material, and, wherein the so-tempered mixture is shapedand compressed into a solid unit dosage form as an oral tablet.

The unit dosage forms prepared by the methods of the invention arecharacterized by uniform and comparable time release characteristics,i.e., the active ingredient is released at comparable rates by each of amultiplicity of tablets formed from a given batch of mixed carriermaterial and therapeutic agent. In contrast to prior art compositionswhich are not tempered according to the invention, the tablet timerelease characteristic is substantially more uniform and batch to batchvariations in time release characteristics are likewise substantiallyreduced.

To achieve uniform and comparable time release of active ingredient or,as stated otherwise, to achieve a uniform and comparable bioavailabilitycharacteristic for each unit dose prepared from a batch of carriermaterial and active ingredient, requires (1) that the same amount ofactive ingredient be present per unit of base material in each unitdosage form and that the active be thoroughly mixed with the base, and,(2) that the thoroughly intermixed active ingredient and carrier basematerial be permitted to reside, in the absence of mixing, for a timesufficient to permit tempering to occur, i.e., a time sufficient topermit the active ingredient to bond to the carrier material by aprocess of physical adherence or chemical-physical adherence.

Whether the base includes one cellulose ether or a mixture of celluloseethers or one or more cellulose ethers having differing viscositycharacteristics, the mixture of that base and the particular activeingredient should not be tableted immediately after mixing the base andthe active ingredient. Following that prior art technique, there is nosatisfactory reproducibility, from tablet to tablet, or from batch tobatch, of the time release characteristic of the unit dosage forms whichare produced. This results in very significant differences in the hourlyrelease times of tablets made from different batches of the samecarrier/active ingredients and results in substantial differences inhourly release times of the active ingredient from tablet to tablet froma given batch of base and active ingredient. This is obviouslyunsatisfactory from a medicinal administration standpoint and may resultto significant medical problems.

It is thought that failure to permit the carrier/active-ingredientmixture to temper may result in a separation of the active ingredientfrom the base material as the mixture is handled during the shaping andcompressing steps which follow the mixing in the prior art. In thisregard, it is observed that the manufacture of controlled releasetablets cannot be properly compared with the manufacture of regular oralpharmaceutical tablets. In the latter case, the important factor is torelease the active ingredient as quickly as possible, whereas uniformand comparable release characteristics are sought with controlled actionformulations.

The exact nature of the bond between the granules of active ingredientand the granules of cellulose ether cannot be precisely characterized.It is understood in the art, however, that methyl cellulose and othercellulosic ethers are useful in adhesives, that they are thermoplasticin nature, that they have thermogelling properties, and that they canbind themselves into self binding tablets. Accordingly, without adoptingany particular theory, it is believed to be central to the instantinvention to permit the active ingredient and the carrier base materialto stand, undisturbed, for a time sufficient to permit the polymericbase material and the active material to bond by whatever physical orphysical-chemical process controls. It is also believed taht the bondingreactions which take place are equilibrium reactions and thataccordingly the benefits of this invention are achieved after atempering period sufficient to permit the bonding action to approach theequilibrium.

The efficacy of the bond between the granular active ingredient and theparticles of the carrier base material is also believed to be affectedby the sizes of the particles themselves and by their configuration.Thus, controling the particle size of the active agent and the basematerial, or their respective particle configurations, so as to create alock-and-key interaction may be of substantial benefit in the temperingprocess and may reduce the amount of time necessary to reach a desiredequilibrium.

It may be possible, to some degree, to control the time releasecharacteristic of formulations containing carrier base material andactive therapeutic agent by varying the length of time that the mixtureis tempered. That is, where a large initial release is necessary toreach a therapeutic level as soon as possible, it may be desirable toshorten the length of the tempering step. In contrast, where a steadyand constant release rate is desirable over a longer period of time, itmay be useful to lengthen the tempering step and enhance the bonding ofthe active ingredient to the carrier base material.

In sustained action drug administration, it is some times desirable tohave a relatively rapid release of active ingredient up to a certainblood level concentration and then to maintain either constant orslightly declining blood level concentration. These objects are achievedwith the invention, whereas in the prior art, as will be demonstrated inthe comparative examples below, wide variations may occur in thebioavailability of the active ingredient where the inventive method isnot employed.

It will be recognized by those skilled in the art that the method of theinvention goes a full step beyond the techniques taught in the UnitedStates Pharmacopoeia for controlling dosage-form uniformity incompressed tablets. The United States Pharmacopoeia--NF, SecondSupplement, describes weight variation and content uniformity tests fortablets. For compressed tablets (coated or uncoated), the prescribedtests require weight variation or content uniformity testing of multipledosage units and a statistical analysis of those results to determinewhether the multiple tablets within a given batch are sufficientlyuniform in their content of active ingredient. The following test isquoted from U.S.P.--NF, Second Supplement, Physical Tests/Uniformity ofDosage Units, page 905.

(A) If the average of the limits specified in the potency definition inthe individual monograph is 100.0 percent or less

COMPRESSED TABLETS (COATED OR UNCOATED), SUSPENSIONS IN SINGLE UNITCONTAINERS, SOLIDS (INCLUDING STERILE SOLIDS) IN SINGLE UNIT CONTAINERS,and STERILE SOLIDS FOR PARENTERAL USE. Unless otherwise specified in theindividual monograph, the requirements for dose uniformity are met ifthe amount of the active ingredient in each of the 10 dosage units asdetermined from the Weight variation of the Content uniformity methodlies within the range of 85.0 percent to 115.0 percent of the tabletclaim and the Relative standard deviation is less that or equal to 6.0percent.

If 1 unit is outside the range of 85.0 percent to 115.0 percent of labelclaim and no unit is outside the range of 75.0 percent to 125.0 percentof label claim, or if the Relative standard deviation is greater than6.0 percent, or if both conditions prevail, test 20 additional units.The requirements are met if not more than 1 unit of the 30 is outsidethe range of 85.0 percent to 115.0 percent of label claim and no unit isoutside the range of 75.0 percent to 125.0 percent of the label claimand the Relative standard deviation of the 30 dosage units does notexceed 7.8 percent.

The foregoing tests, whether based on weight variation or contentuniformity, are not ultimately suitable for proper reliability testingof unit-dosage forms from a batch of intended time release formulation.That is because even with a satisfactory statistical performance withrespect to weight variation and content uniformity, the time releasecharacteristics of active ingredient from such tablets may vary markedlybecause the active ingredient has not been permitted to bond to thecarrier material according to the instant invention.

The invention is not limited to the use of any particular celluloseethers, and those skilled in the art will recognize that a singlecellulose ether or mixture of ethers can be used as can a variety ofviscosity grades of the several commercially available cellulose ethers.Broadly, it is preferred to use hydroxyalkyl cellulose and/orhydroxyalkly alkylcellulose such as hydroxypropyl methylcellulose,hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl celluloseand other similar compounds or derivatives. Preferred among these arehydroxypropyl methylcellulose and hydroxypropyl cellulose, the formerbeing obtainable in a variety of viscosity grades from 3 cps to 100,000cps from Dow Chemical Company under its trade name Methocel and thelatter being available from Hercules, Inc., under its trademark Klucel.Advantageous carrier bases can be prepared using Methocel E50 (50 cps),Methocel E4M (4,000 cps), and Methocel K15M (15,000 cps).

The active ingredients combined with the carrier base material can be ofany type which acts systemically or locally. Those which actsystemically are typically administered orally, the object being todeliver reliable and constant amounts of active agent into the bloodstream. Those types of active ingredients which act locally may beemployed in buccal tablets or in vaginal or rectal suppositories.

Among the active therapeutic agents which can be combined with carrierbase material according to the method of the invention are sedatives,vitamins, anti-inflammatory agents, vasodilators, stimulants, relaxants,suppressants, and many other types of therapeutic agents.

Among the active ingredients which can be used in the method of theinvention are, for example, isosorbide dinitrate or mononitrate(employed in the treatment of angina pectoris), theophylline (employedin the treatment of asthma), nitroglycerin, ibuprofen, andacetaminophen.

In preparing the pharmaceutical compositions of the invention, thedesired ratio of active ingredient and a carrier base material isintroduced into a mixing vessel. Other ingredients to be included in thefinal unit dosage form may be introduced into the mixing vessel, forexample, fillers, drying agents, lubricants, coloring agents, starch,and other materials well known in the art. Thereafter the base mixtureis typically agitated and mixed for from 20 to 40 minutes and usuallyfrom 30 to 40 minutes to achieve uniformity of the active ingredientswith the base mixture. Mixing equipment may be, for example, a Day mixeror a Pony mixer.

The tempering step which is critical to the instant invention is usuallycarried out in the same or a different vessel from that in which themixing has taken place. The uniformly mixed material is permitted tostand, substantially undisturbed for a period of 2 to 72 hours,preferably 4 to 48 hours, while the active ingredient bonds to theplastic carrier base material.

After the uniform mixture has been tempered for a sufficient time tocause the bonding to take place, it is transferred to a shaping andcompressing step as is well known in the art. The equipment used forsuch steps may be, for example, Stokes or Colton rotary machines orother tablet compressing machines. Typical compression used in theshaping and compressing step varies from 6 to 12 kg/cm² and preferablyis in the range of 8 to 12 kg/cm². The unit dosage forms prepared inthis final step are oral tablets.

The invention is further described in the following examples and in thedrawings.

EXAMPLES

A series of sustained release oral tablets were prepared by the methodof the invention and by the prior art method and their respectivesustained release performance was tested.

EXAMPLES I-IV Method of Oral Tablet Preparation

The base ingredients listed below were mixed for about 20 minutes in aDay powder mixer or a Pony mixer. Active ingredient was added to thebase mixture and the mixture was again mixed for about 30 minutes addinglubricants. Finally the complete mixture was permitted to temper forbonding for not less than 24 hours at room temperature. The tablets werecompressed into scored capsule-shaped oral tablets. The punch size was19 mm×8.5 mm and the hardness was 9 kg/cm². In each instance, thepotency of the tablet was 120 mg.

Release of Active Ingredient

The release of active ingredient from the tablets prepared in ExamplesI-IV was determined by blood level tests performed, in each instance, onsix volunteers. The volunteers were all healthy adults. Each volunteerunderwent a careful medical examination before the first treatment,including measurement of arterial blood pressure and pulse rate, bloodcell count, blood glucose, urea, creatinine, bilirubin and a completeurinalysis. The mean age of the volunteers was about 36 years and theaverage body weight was about 70 kilograms. All doses were administeredafter fasting conditions by the oral administration and ingestion of thetablets with 100 ml of tap water. The mean value of the blood level ofactive ingredient at the indicated time intervals is shown in FIGS. 1-4.

The release of active ingredient over time from the tablets prepared asdescribed above can also be determined by an in vitro assay whichanalyzes the percent of the drug released by a single tablet at six timeintervals by means of the dissolution test "paddle" apparatus (U.S.P.XX, page 959). In this test, one tablet is placed in a vessel containing500 ml of pH 1.2 buffer (simulated gastric fluid without enzymes, U.S.P.XX, page 1105) and kept under 125 RPM rotation at 37° C. during thetest. At the first, fourth, and eighth hours, the absorbence of thesolution is determined at about 278 nm against a pH of 1.2.

The following oral tablets were prepared:

EXAMPLE I

    ______________________________________                                        Active ingredient X   120 gm                                                  Hydroxypropyl methylcellulose                                                 HPMC E-50 (Dow)       10 gm                                                   HPMC E-4M (Dow)       50 gm                                                   Hydroxypropyl cellulose                                                                             10 gm                                                   HPC (Hercules)                                                                Stearic Acid          1 gm                                                    Syloid                2 gm                                                    ______________________________________                                    

EXAMPLE II

    ______________________________________                                        Active ingredient X                                                                             120 gm                                                      HPMC E-50         30 gm                                                       HPMC E-4M         30 gm                                                       HPC               10 gm                                                       Stearic Acid      1 gm                                                        Syloid            2 gm                                                        ______________________________________                                    

EXAMPLE III

    ______________________________________                                        Active ingredient X                                                                             120 gm                                                      HPMC E-50         40 gm                                                       HPMC E-4M         20 gm                                                       HPC               10 gm                                                       Stearic Acid      1 gm                                                        Syloid            2 gm                                                        ______________________________________                                    

EXAMPLE IV

    ______________________________________                                        Active ingredient X                                                                             120 gm                                                      HPMC E-50         10 gm                                                       HPMC E-4M         50 gm                                                       HPC               10 gm                                                       Stearic Acid      1 gm                                                        Syloid            2 gm                                                        ______________________________________                                    

COMPARATIVE EXAMPLES I-A-IV-A

Oral tablets were prepared according to the prior art method using thesame mixtures as are described in Examples I-IV. The tablets of ExamplesIA-IVA were prepared by mixing the base ingredients listed above forabout twenty minutes in a Day powder mixer or pony mixer, adding activeingredient to the base mix and then mixing same again for about thirtyminutes while adding lubricants. Then, the mixture was tabletedimmediately without permitting it to stand or become bonded according tothe invention. As in Examples I-IV, the tablets were compressed intoscored capsule-shaped tablets using a punch size of 19 mm×8.5 mm and ahardness of 9 kg/cm². Release of active ingredient was determined asdescribed in Examples I-IV.

Comparison of Oral Tablets of The Invention With Oral Tablets of ThePrior Art

FIG. 1 shows curves of the amount of active ingredient released from thetablet of Example I, reference numeral 10, and from the tablet ofExample I-A, reference numeral 12, respectively. It is apparent that thecomparative tablet, tablet I-A, which was prepared from a batch notpermitted to bond, shows a sharp drop in active ingredient level atabout three hours. Moreover, the amount of active ingredient availableafter twelve hours is substantially lower than in the tablet preparedaccording to the invention which was permitted to bond for at leasttwenty-four hours. Moreover, the active ingredient released from thetablet prepared according to the invention had a substantially evenrelease characteristic after reaching its highest active ingredientlevel at about two hours.

FIG. 2 shows curves of the amount of active ingredient released from thetablet of Example II, 14, and from the tablet of Example II-A, 16,respectively. The release of active ingredient depicted in FIG. 2substantially confirms the superiority of the bonded tablet. There is anextremely sharp drop in active level at about three hours from thetablet prepared according to the prior art (Example II-A).

FIG. 3 shows curves of the amount of active ingredient released from thetablet of Example III, 18, and from the tablet of Example III-A, 20,respectively. The results again confirm the superiority of the tabletsprepared according to the invention. The drop in active level fromcomparative tablet III-A was extremely sharp in the third hour.

FIG. 4 shows curves of the amount of active ingredient released from thetablet of Example IV, 22, and from the tablet of Example IV-A, 24,respectively. The superiority of the tablet of the invention isconfirmed, there being an extremely sharp drop in active level from theunbonded tablet (IV-A) at about the third hour.

EXAMPLE V Method of Tablet Preparation

The base ingredients listed below are mixed for about 20 minutes in aDay powder mixer or a Pony mixer. Active ingredient was added to thebase mixture and the mixture was again mixed for about 30 minutes addinglubricants. Finally the complete mixture was permitted to temper forbonding for not less than 24 hours at room temperature. The tablets werecompressed into scored capsule-shaped oral tablets. The punch size was19.1 mm×9.7 mm and the hardness was 9 kg/cm². In each instance, thepotency of the tablet was 85 mg.

Release of Active Ingredient

The release of active ingredient from the tablets prepared in Example Vwas determined by blood level tests performed, in each instance, on sixvolunteers. The volunteers were all healthy adults. Each volunteerunderwent a careful medical examination before the first treatment,including measurement of arterial blood pressure and pulse rate, bloodcell count, blood glucose, urea, creatinine, bilirubin and a completeurinalysis. The mean age of the volunteers was about 36 years and theaverage body weight was about 70 kilograms. All doses were administeredafter fasting conditions by the oral administration and ingestion of thetablets with 100 ml of tap water. The mean value of the blood level ofactive ingredient at the indicated time intervals is shown in FIG. 5.Venous blood samples were obtained from each subject just prior to andat 0.25, 0.5, 0.75, 1.00. 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 9.0, 12.0, 24.0,36.0 and 48.0 hour times after dosing. In all six (6) subjects, arterialblood pressure was also measured just prior to dosing, and at 1.0, 2.0,4.0, 6.0 and 9.0 hours after dosing.

The release of active ingredient over time can also be determined by anin vitro assay. This assay determines the percent of the drug releasedby a single tablet at fixed time intervals by means of a dissolutiontest "paddle" apparatus (U.S.P. XX, page 959). One tablet is placed inthe vessel containing 500 ml of pH 1.2 buffer (simulated gastric fluidwithout enzymes, U.S.P. XX, page 1105) and kept under 125 RPM rotationat 37° C. during the test. At the first, fourth and eighth hours,samples are withdrawn and treated with hydrazine sulfate, sulfanilamidand N-(1-naphthyl)-ethylenediamine hydrochloride and the absorbence ofthe solution is determined at about 540 mm.

The following mixture was prepared and tableted as above.

    ______________________________________                                        Active ingredient Y                                                                             80 gm                                                       HPMC E-50         20 gm                                                       HPMC E-4M         40 gm                                                       HPMC K-15         10 gm                                                       HPC               10 gm                                                       Stearic Acid      1 gm                                                        Syloid            1 gm                                                        ______________________________________                                    

COMPARATIVE EXAMPLE V-A

The base ingredients listed in Example V were mixed for about 20 minutesin a Day powder mixer or a Pony mixer. Active ingredient was added tothe base mixture and the mixture was again mixed for about 30 minutesadding lubricants. The mixture was then tableted immediately in a StokesB2 Rotary machine or Manesty machine set to a compression of 9 kg/cm².The tablets were compressed into scored, capsule-shaped tablets. Thepunch size was 19.1 mm× 9.7 mm and the hardness was 9 kg/cm². In eachinstance, the potency of the tablet was 85 mg. Release of activeingredient was determined as described in Example V.

Comparison of Tablets of The Invention With Tablets of The Prior Art

FIG. 5 shows curves of the release of active ingredient from the twosets of oral tablets of Example V, 26, prepared according to theinvention and one set of oral tablets prepared according to prior artmethod (Example V-A) 28. It is clear that the unbonded tablet (ExampleV-A) reached the highest active level almost immediately and then therelease suffered a sharp drop at the third hour. The active level fromthe tablet of comparative example V-A was substantially lower in thelater hours of the test than from either of the tablets preparedaccording to the method of the invention.

EXAMPLE VI Method of Tablet Preparation

The base ingredients listed below were mixed for about 20 minutes in aDay powder mixer or a Pony mixer. Active ingredient was added to thebase mixture and the mixture was again mixed for about 30 minutes addinglubricants. Finally the complete mixture was permitted to temper forbonding for not less than 24 hours at room temperature. The mixture wasthen tableted in a Stokes B2 rotary machine or a Manesty machine set toa compression of 9 kg/cm². The tablets were compressed into scoredcapsule-shaped tablets. The punch size was 19.1 mm×9.7 mm and thehardness was 9 kg/cm². In each instance, the potency of the tablet was104 mg.

The following formulation was prepared:

    ______________________________________                                        Active ingredient Z                                                                             100 gm                                                      HPMC E-50         20 gm                                                       HPMC E-4M         40 gm                                                       HPMC K-15         10 gm                                                       HPC               10 gm                                                       Stearic Acid      1 gm                                                        Syloid            1 gm                                                        ______________________________________                                    

Release of Active Ingredient

The release of active ingredient from the tablets prepared in Example VIwas determined by blood level tests performed, in each instance, on sixvolunteers. The mean value of the blood level of active ingredient atthe indicated time intervals is shown in FIG. 6. Venous blood sampleswere obtained from each subject just prior to and at 0.25, 0.5, 0.75,1.00. 1.5, 2.0, 2.5, 3.0, 4.0, 6.0, 9.0, 12.0, 24.0, 36.0 and 48.0 hourtimes after dosing. In all six (6) subjects, arterial blood pressure wasalso measured just prior to dosing, and at 1.0, 2.0, 4.0, 6.0 and 9.0hours after dosing.

The release of active ingredient over time can also be determined by anin vitro assay. This assay determines the percent of the drug releasedby a single tablet at fixed time intervals by means of a dissolutiontest "paddle" apparatus (U.S.P. XX, page 959). One tablet is placed inthe vessel containing 500 ml of pH 1.2 buffer (simulated gastric fluidwithout enzymes, U.S.P. XX, page 1105) and kept under 125 RPM rotationat 37° C. during the test. At the first, fourth and eighth hours,samples are withdrawn and treated with hydrazine sulfate, sulfanilamidand N-(1-naphthyl)-ethylenediamine hydrochloride and the absorbence ofthe solution is determined at about 540 nm.

COMPARATIVE EXAMPLE VI-A Method of Oral Tablet Preparation

The base ingredients listed in Example VI are mixed for about 20 minutesin a Day powder mixer or a Pony mixer. Active ingredient is added to thebase mixture and the mixture is again mixed for about 30 minutes addinglubricants. The mixture is then immediately tableted in a Stokes B2Rotary machine or Manesty machine set to a compression of 9 kg/cm². Thetablets were compressed into scored, capsule-shaped tablets. The punchsize was 19.1 mm×9.7 mm and the hardness was 9 kg/cm². In each instance,the potency of the tablet was 104 mg. Release of active ingredient wasdetermined as in Example VI.

FIG. 6 describes the release of active ingredient from two sets oftablets of Example VI prepared according to the invention, 30, and acommercially available oral tablet of the prior art, 32. FIG. 6 showsthat both tablets prepared according to the invention acted in a similarmanner over a period of twelve hours.

EXAMPLE VII

On a different day, a control (comparison) batch of product Z was madewith the same formula as Example VI and the finished tablets were testedagain the same way as in Example VI for comparison of results. FIG. 7,reference numeral 34, demonstrates that the release of active ingredientfrom two bonded tablets was substantially the same as the release ofactive ingredient from the tablets prepared earlier as described inExample VI.

What is claimed is:
 1. A method of preparing uniform batches of unitdoses, wherein each of the unit doses has uniform bioavailability, frombatch to batch, of a controlled long-acting release pharmaceuticalformulation containing an active therapeutic agent and a carrier basematerial, in unit dosage form, comprising the steps of:(a) thoroughlymixing a carrier base material comprising at least one cellulosic etherwith a therapeutic agent to form a substantially uniform pharmaceuticalformulation; (b) discontinuing the mixing step and permitting themixture formed in step (a) to stand for a period of time sufficient tocause the said therapeutic agent to become bonded to the said cellulosicether; and (c) compressing the said pharmaceutical formulation into asuitable unit dosage form wherein release, from batch to batch, is notfaster, from one unit dosage to another.
 2. A method as recited in claim1 wherein the carrier comprises one or more hydroxyalkyl cellulose orhydroxyalkyl alkylcellulose.
 3. A method as recited in claim 1 whereinthe carrier comprises one or more of the cellulose ethers hydroxypropylmethylcellulose, hydroxypropyl cellulose; carboxymethyl cellulose andethylcellulose, or derivatives.
 4. A method as recited in claim 1wherein the mixture formed in step (a) is permitted to stand for atleast 2 hours before compression into a unit dosage form.
 5. A method ofpreparing uniform batches of unit doses, wherein each of the unit doseshas uniform bioavailability, from batch to batch, of a multiplicity ofunit doses of a controlled long-acting release pharmaceuticalformulation containing an active therapeutic agent and a carrier basematerial, wherein each of said unit doses, when consumed, releases saidagent over time in a substantially uniform and comparable fashion, saidmethod comprising the steps of:(a) adding a quantity of solid,particulate, carrier base material consisting essentially of one or morecellulosic ethers selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropyl cellulose, carboxymethyl cellulose andethylcellulose or derivatives to a quantity of a therapeutically activepharmaceutical agent in granular or powder form; (b) mechanically mixingthe base material and active therapeutic agent to form a uniformmixture; (c) discontinuing the mixing and permitting the mixture formedin step (a) to stand for a period of time sufficient to cause the saidgranules of active therapeutic agent to become bonded to the particlesof carrier base material; and (d) compressing portions of the mixtureformed in steps (b) and (c) into solid unit doses in the form oflozenges, buccal tablets, oral tablets or suppositories wherein release,from batch to batch, is not faster, from one unit dosage to another. 6.A method as recited in claim 5 wherein the mixture formed in step (a) ispermitted to stand for at least 2 hours before compression into a unitdosage form.
 7. A method as recited in claim 5 wherein the mixtureformed in step (a) is permitted to stand for from 4 to 24 hours beforecompression into a unit dosage form.
 8. A method as recited in claim 5wherein the carrier is hydroxypropyl methylcellulose or derivatives. 9.A method as recited in claim 5 wherein the carrier is a mixture ofhydroxypropyl methylcellulose and hydroxypropyl cellulose orderivatives.
 10. A method of preparing uniform batches of unit doses,wherein each of the unit doses has uniform bioavailability, from batchto batch, of a multiplicity of unit doses of a controlled long-actingrelease pharmaceutical formulation containing an active therapeuticagent and a carrier base material, wherein the bioavailability of saidtherapeutic agent from each unit dosage form is substantially uniformand comparable, said method comprising the steps of:(a) adding aquantity of solid, particulate, carrier base material consistingessentially of at least one cellulosic ether, selected from the groupconsisting of hydroxypropyl methylcellulose, hydroxypropyl cellulose,carboxymethyl cellulose and ethyl cellulose, to a quantity oftherapeutically active pharmaceutical agent in granular or powder form;(b) mechanically mixing the carrier base material and therapeuticallyactive pharmaceutical agent to form a uniform mixture; (c) discontinuingthe mixing and permitting the mixture formed in step (a) to stand for aperiod of time from 2-72 hours to cause the therapeutically activepharmaceutical agent to become bonded to particles of the carrier basematerial; and (d) compressing portions of the mixture formed in steps(b) and (c) into solid oral tablet unit doses wherein release, frombatch to batch, is not faster, from one unit dosage to another.